While remarkable progress has been made in the management of depressive attacks, the leading psychiatric cause for hospital admission, comparatively little has been done to prevent their occurrence. Prevention depends upon the identification of individuals at high risk, and this in turn depends upon the elucidation of risk factors. A risk factor must be related to the trait of being vulnerable to an illness rather than to the state of being ill. For depression there is at present no ideal risk factor, one that is highly specific and highly sensitive. Of the various somatic findings that hold promise a blunted thyrotropin (TSH) response to thyrotropin releasing hormone (TRH) is prominent. This occurs in about 25% of depressed and alcoholic patients but not in schizophrenics. In at least some patients it is related to trait rather than state, and preliminary evidence suggests that it occurs in some relatives of depressed probands. A blunted TSH response, occurring in depressed and alcoholic patients, may be a biological finding that runs parallel to the familial association of these disorders. We propose to evaluate the value of TSH blunting as a risk factor by studying four populations: normal subjects, probands with affective disorder and their relatives, and relatives of probands with alcoholism. As a first step, we will study a large number of normal subjects. This has three specific aims: to refine the definition of TSH blunting; to discover possible relationships between TSH blunting and a family history of depression or alcoholism; to evaluate the value of the TSH respose as a predictor for future psychopathology. We then will study probands with affective disorder and their relatives. Again the specific aims are threefold: to evaluate the incidence of TSH blunting in affected families; to evaluate the value of TSH blunting as a predictor of psychopathology; to investigate stability and reliability of the fault during changing states of psychopathology. Finally, we propose to study relatives of probands with chronic alcoholism. As with affective disorders, the main thrust is the evaluation of the incidence of TSH blunting in relatives of alcoholics and the determination of the value of the fault in endocrine response as a predictor of psychopathology.